Idebenone is a synthetic, small molecule analogue of coenzyme Q10 (CoQ10), the vital cell membrane antioxidant and essential constituent of the adenosine-triphosphate (ATP)-producing mitochondrial electron transport chain (ETC). Idebenone has the ability to operate under low oxygen tension situations. Due to its ability to inhibit lipid peroxidation, idebenone protects cell membranes and mitochondria from oxidative damage (Zs.-Nagy I (1990) Chemistry, toxicology, pharmacology and pharmacokinetics of idebenone: a review. Arch. Gerontol. Geriatr. 11:177-186). It's antioxidant properties protect against cerebral ischemia and nerve damage in the central nervous system. More importantly, Idebenone also interacts with the ETC, preserving ATP formation in ischemic states. This compound is already used as a nootropic drug and has also been shown to stimulate nerve growth factor, a characteristic that could be important in the treatment of Alzheimer's and other neurodegenerative diseases. Idebenone is described in the specification of Japanese Patent Examined Publication No. 3134/1987 filed by Takeda Chemical Industries, Ltd. In addition it has been shown that idebenone can be applied in the treatment of diseases associated with iron overload, particularly Friedreich Ataxia (U.S. Pat. No. 6,133,322).
As a lipophilic compound Idebenone is well absorbed in the gastrointestinal tract after conventional oral administration, which is the normal route for administering said compound. Dosage forms such as tablets or capsules have been used in clinical trials and as marketed product. In WO 2008/019769 the pharmacological profile of conventionally administered Idebenone is described and the authors suggest to use Idebenone in a transmucosal formulation.
Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of the central nervous system (CNS) that destroys myelin, oligodendrocytes, axons and neurons (Noseworthy, J. H., C. Lucchinetti, et al. (2000). Multiple sclerosis. N Engl J Med 343(13): 938-52). The vast majority of newly-diagnosed MS patients develop the relapsing-remitting form of the disease (RRMS), in which periods of neurological worsening are followed by periods of spontaneous remission, at least at the beginning of the disease process. About 10-15% of patients develop primary progressive MS (PP-MS), characterized by progressive accumulation of neurological disability from the disease onset, without any superimposed worsening (i.e. relapses) or improvements (remissions) (Miller, D. H., S. M. Leary (2007). Primary-progressive multiple sclerosis. Lancet Neurol 6(10): 903-12).
Primary progressive MS (PP-MS) patients differ from RRMS patients in several important characteristics: They tend to be older at the time of disease onset (mean 40 vs. 30 years); males and females tend to be affected equally; clinically there is a high prevalence of cortico-spinal dysfunction characterized by progressive weakness and spasticity; patients have more prominent involvement of the spinal cord (Bieniek, M., D. R. Altmann, et al. (2006). Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 77(9): 1036-9) and generally lower amount of distinct white matter lesions (i.e. plaques) in the brain and less evidence for brain inflammatory activity (Lucchinetti, C. and W. Bruck (2004). The pathology of primary progressive multiple sclerosis. Mult Scler 10 Suppl 1: S23-30) and, most importantly, PP-MS patients do not respond to immunomodulatory therapies with proven efficacy in RRMS (Leary, S. M. and A. J. Thompson (2005). Primary progressive multiple sclerosis: current and future treatment options. CNS Drugs 19(5): 369-76).
Both new imaging modalities and pathological data suggest that in PP-MS, CNS pathology is more diffuse (Filippi, M., M. A. Rocca, et al. (2002). Correlations between structural CNS damage and functional MRI changes in primary progressive MS. Neuroimage 15(3): 537-46; Rovaris, M., E. Judica, et al. (2008). Large-scale, multicentre, quantitative MRI study of brain and cord damage in primary progressive multiple sclerosis. Mult Scler. 14(4): 455-64) and occurs to some extent independently of focal lesions (Sastre-Garriga, J., G. T. Ingle, et al. (2004). Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis. Neuroimage 22(1): 353-9.; Kutzelnigg, A., C. F. Lucchinetti, et al. (2005). Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128 (Pt 11): 2705-12; Rovaris, M., A. Gallo, et al. (2005). Axonal injury and overall tissue loss are not related in primary progressive multiple sclerosis. Arch Neurol 62(6): 898-902).
The cervical spinal cord is the major target of the disease process in PP-MS, underlying most of the clinical disability. The diffuse CNS process in PP-MS is characterized by microglial activation and diffuse axonal injury in the white matter and by cortical demyelination and neuronal loss in the gray matter. Additionally, low level but persistent endothelial abnormalities and blood-brain-barrier (BBB) leak, both in normal appearing white and gray matter have been observed.
There are currently no treatments with proven therapeutic efficacy for PP-MS (Leary, S. M. and A. J. Thompson (2005). Primary progressive multiple sclerosis: current and future treatment options. CNS Drugs 19(5): 369-76). Neither interferon-beta preparations (Leary, S. M., D. H. Miller, et al. (2003). Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 60(1): 44-51; Montalban, X. (2004). Overview of European pilot study of interferon beta-1b in primary progressive multiple sclerosis. Mult Scler 10 Suppl 1: S62; discussion 62-4) nor glatiramer acetate (Wolinsky, J. S., P. A. Narayana, et al. (2007). Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 61(1): 14-24) could slow down the accumulation of disability in PP-MS. Several Phase II trials of Mitoxantrone in PP-MS were initiated, but none reported positive effect. A recently reported large multicentric, placebo-controlled Phase II trial of Rituximab in PP-MS also failed to demonstrate any effect on the accumulation of disability in this patient population (see http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=221.)
These data collectively indicate that therapies targeting the immune system and specifically the formation of Gd-enhancing MS lesions do not demonstrate beneficial effect in PP-MS. In agreement with the reviewed hypothesis that the pathophysiology of PP-MS may rely more on neurodegenerative, rather than immune-mediated mechanisms of CNS tissue destruction, a pilot trial of the neuroprotective agent riluzole showed a mild effect on inhibiting the development of cervical cord atrophy in the PP-MS cohort (Kalkers, N. F., F. Barkhof, et al. (2002). The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler 8(6): 532-3) which however, did not reach statistical significance.
In another study (A. Bosco, G. Cazzato, et al., Nuova Rivista di Neurologia, 7 (1997), 90-94) with patients suffering from the chronic-progressive form of MS, which is clinically distinct from PP-MS, idebenone (at a dose of 90 mg/day) given in combination with methylprednisolone over 240 days could not be shown to have any clinical or neurophysiological efficacy.
Accordingly, there is a strong need in the art to provide further means for treating and/or preventing several symptoms associated with of primary progressive Multiple Sclerosis.
Said object is achieved by providing Idebenone for preparing a medicament for curative treating or preventing of primary progressive Multiple Sclerosis.